ABSTRACT Sinoatrial node (SAN) dysfunction (SND) is associated with abnormal impulse formation and propagation in the SAN. Recent estimates suggest that >75,000 new cases of SND occur in the U.S. every year and that this number will more than double by 2060. At present, surgical implantation of permanent pacemakers remains the most efficient treatment of SND which, however, is limited when compared with pharmacologic therapy and costs $2 billion annually in the U.S. Contemporary evidence suggests an emerging role of compartmentalized remodeling (i.e. associated with distinct, spatially-confined micro-domains) of pacemaker proteins in SND. Our studies and others have demonstrated that the proteins involved in pacemaking activity are associated with specific membrane microdomains, caveolae, i.e., small (50?100 nm) invaginations of the plasma membrane enriched by cholesterol, sphingolipids and scaffolding proteins caveolin-3 (Cav3). Here, we propose that Cav3 organizes specialized pacemaker signaling complexes providing functional coupling between the sarcolemmal proteins (referred to as a surface ?membrane clock?) and subcellular Ca2+ machinery (referred to as an ?intracellular Ca2+ clock?). We hypothesize that disruption in subcellular targeting of pacemaker proteins and associated signaling molecules upon structural remodeling of the SAN, may affect their biophysical properties and neurohormonal regulation as well as protein-protein interactions within the pacemaker signaling complex disturbing rhythmic generation of action potentials and thus contributing to the pathophysiology of the SND. This research introduces a novel concept of electrophysiological changes resulting from alternations in the subcellular compartmentalization of signaling complexes following structural remodeling. This extends beyond the classical concept of electrical remodeling, according to which dysfunction can be explained by straightforward increases or decreases in protein expression alone, and adds a new dimension to cardiovascular disease. This research will open completely new avenues for sophisticated and more effective therapeutic approaches targeted at preventing the degradation of cardiac cytoarchitecture.